1. Graeme Meintjes University of Cape Town Imperial College London
Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS)
Graeme Meintjes
University of Cape Town
Imperial College London
Webinar
25 Nov 2013

2. Restoration of pathogen-specific immunity
ART
Viral suppression
(CD4 rise)
Restoration of pathogen-specific immunity - +
Regression or prevention of opportunistic infections
Inflammatory reactions days to
months after starting ART = IRIS
IRIS = Immune Reconstitution Inflammatory Syndrome
IRD = Immune Restoration Disease

3. Wide range of IRIS conditions described
Mycobacteria TB
MAC
Leprosy
BCG
Other NTM
Fungi
Cryptococcus
Histoplasmosis
PCP
Dermatophytes
Candida
Aspergillus
Penicillium
Viruses
Hepatitis B and C
HSV 1 and 2
HZV
CMV
JC virus
BK virus
Molluscum
Warts
Parvovirus B19
HIV dementia
Protozoans
Toxoplasmosis
Leishmaniasis
Microsporidia
Cryptosporidia
Helminths
Schistosoma
Strongyloides
Bacteria
Bartonella
Other skin conditions
Acne and folliculitis
Auto-immune and inflammatory conditions
Guillain-Barre syndrome
Sarcoidosis
Grave’s
Peyronie’s
Rheumatological conditions (SLE, RA, Reiter’s)
Tattoo pigment and foreign body reactions
Cerebral vasculitis
TTP
LIP
Tumours
Kaposi’s sarcoma, lymphoma

4. ART Paradoxical Patients on TB-IRIS TB treatment ART ART-associated TB
Patients not on
TB treatment
TB-IRIS is characterised by clinical deterioration during ART thought to result from an immunopathological reaction to MTB antigen as MTB-specific immune reposes improve.
It may manifest in one of two forms:
Patients on TB treatment experience a paradoxical reaction after starting ART.
Among patients not on TB treatment when they start ART TB incidence rates remain high especially during the first months of ART in RLS. A subset who manifest with TB that has a particularly exaggerated inflammatory presentation that in the first 3 months of ART are regarded as having unmasking TB-IRIS
Unmasking TB-IRIS

5. OVERVIEW Clinical presentations Diagnosis
Neurological TB-IRIS
Hepatic TB-IRIS
Prolonged TB-IRIS
Diagnosis
Corticosteroids for treatment
ART timing
Prevention trial
Focus clinical, not pathogenesis

6. What is the typical time of onset of paradoxical TB-IRIS after ART start?
3-10 days
1-4 weeks
4-8 weeks
Around 3 months

7. Paradoxical TB-IRIS Patient diagnosed with TB and
started on TB treatment
Improving on TB
treatment then starts ART
Fever
Recurrence of TB symptoms and new or recurrent clinical manifestations of TB
(Usually 1-4 weeks after starting ART)

8. Paradoxical TB-IRIS characteristics
Incidence 8 – 54% (15.7% in meta-analysis)
Onset of symptoms: Median 14 days from ART start
Focal and systemic inflammatory features
Fever, tachycardia, weight loss
Hospitalisation in up to 48%
Median duration 2-3 months
Mortality infrequent
Meta-analysis 3.2% (substantially higher if CNS IRIS)
Meintjes Lancet Infect Dis 2008;8:516, Muller Lancet Infect Dis 2010;10:251, Agarwal AIDS Res Ther 2012;9:17,
Meintjes Clin Infect Dis 2009;48:667, Burman IJTLD 2007;11:1282

10. Worsening pulmonary infiltrate and cavitation due to TB-IRIS
CXR 3 – one week later
Worsening pulmonary infiltrate and cavitation due to TB-IRIS

11. Massive psoas abscess

13. (1 litre drained at pericardiocentesis)
Pericardial tamponade due to paradoxical TB-IRIS
TITLE: LIFE THREATENING COMPLICATIONS
ADD MASSIVE TUBERCULOMA CASE
SPLENIC RUPTURE
3 weeks on ART
(1 litre drained at pericardiocentesis)
On TB treatment prior to ART

14. Neurological TB-IRIS 12% with paradoxical TB-IRIS have CNS involvement
Up to 47% of TBM patients starting ART develop IRIS
Features
Meningitis
Tuberculoma/s
Radiculomyelopathy
Occurs in patients with or without CNS TB prior to ART
Outcomes
13% mortality and 18% loss to follow-up in one series
25% and 75% mortality in other series
Neurological disability
75% no neuroTB prior to ART Pepper
Pepper et al, Clin Infect Dis 2009
Marais et al, Clin Infect Dis 2012
Agarwal et al, AIDS Res Ther 2012

15. TBM diagnosis
TBM-IRIS
Slide courtesy Suzaan Marais

16. TBM-IRIS with expressive aphasia
Slide courtesy Suzaan Marais

17. TB-IRIS with enlarging mass lesion/cerebral oedema
TBM and PTB prior to ART
TB-IRIS with enlarging mass lesion/cerebral oedema
Patient died

18. CSF Neutrophils and TBM-IRIS
Non IRIS
p=0.01
p<0.0001
Cells/mm3
Marais
CID 2012
TBM diagnosis
Day 0
ART Start
Day 14
2 weeks post ART/IRIS
Day 28
P=0.007

19. Hepatic TB-IRIS is characterised by which of the following?
Severe jaundice on clinical examination
Elevation in transaminases more then 10 x upper limit of normal
Non-tender hepatomegaly
The most prominent LFT abnormality being elevation of Alk Phos and GGT.

20. Hepatic TB-IRIS case
4 months treatment for drug-sensitive pericardial TB
Clinically improved, then started ART
3 weeks later presented with fever and hepatomegaly
LFT: Bil 52, CBil 31, Alk Phos 1081, GGT 1468, ALT 82, AST 88
CD4 rise from 64 to 221
Biopsy AFB- and TB culture -
Case courtesy of Mark Sonderup
Low power - several well formed granulomas
Medium power - large well formed granuloma
High power - Multinucleated epitheloid giant cell with surrounding lcytes, plasma cells and eos

21. Hepatic TB-IRIS vs DILI
RUQ pain, nausea and vomiting
Tender hepatomegaly
Cholestatic LFT derangement
+/- mild jaundice
Usually other TB-IRIS
manifestations
Drug-induced liver injury
Similar symptoms
Typically not hepatomegaly
Transaminitis +/- jaundice
Absence of other TB-IRIS features
Patients may present with
clinical picture between these two
- Biopsy or treat as DILI
Two conditions may co-exist

22. Prolonged TB-IRIS Typically suppurative lymphadenitis & abscesses
Systemically well
Tuberculomas & cerebral abscesses
TB-IRIS duration (n = 176)
Median: 70 days
IQR: days
IRIS > 90 days: 36%
Bana, unpublished

23. Prolonged TB-IRIS: Management
Often repeated aspirations required
Avoid surgical drainage
Repeat TB culture and susceptibility testing
Corticosteroids for > 4 months questionable unless CNS involved
Experimental therapies
Thalidomide and TNF-α blockers
Consider prolonging TB treatment
How adequate is drug penetration?
For sterilisation

24. Key points in TB-IRIS diagnosis
Diagnosis of TB confirmed or very likely?
Improvement on TB treatment prior to ART?
Symptom onset typically 1-4 weeks on ART
Deterioration with inflammatory features of TB
Consider and exclude differential diagnoses
Exclude drug-resistant TB
There is no confirmatory diagnostic test

25. 100 TB-IRIS suspects screened using case definition KEY FINDING
Undiagnosed rifampicin resistance in 10.1% of patients (95% CI %) presenting with TB-IRIS, after exclusion of known rifampicin resistance and alternative opportunistic diseases
Meintjes Clin Infect Dis 2009;48:667

26. Lymph node enlargement
Differential diagnoses
Lymphoma
Kaposi’s
Castleman’s disease
Consider malignancy particularly when LN remains firm
NTM IRIS
Cryptococcal IRIS
Firm nodes

27. Other important differential diagnoses
Manifestation
Differential diagnoses
Pulmonary infiltrate
Bacterial pneumonia
PCP
Kaposi’s sarcoma
Pleural effusion
Bacterial empyema
Meningitis
Bacterial
Cryptococcal
Space-occupying lesion
Toxoplasmosis
Cryptococcoma
Primary CNS lymphoma
Fever with general deterioration
Bacterial sepsis
NTM
Kaposi’s or lymphoma
*Consider and investigate for DR-TB in all scenarios

28. Pathogenesis of paradoxical IRIS
Recovery of pathogen-specific
immune responses and T-cell
activation
Recovery of innate immune
function
Inflammatory reactions directed to antigens of opportunistic infection
Pro-inflammatory cytokines and chemokines
Defective immune
regulatory function

29. Prednisone for TB-IRIS: which statement is correct?
Prednisone has been shown to reduce the risk of death from TB-IRIS
Prednisone should be prescribed to prevent TB-IRIS in high risk patients
When prednisone is used to treat TB-IRIS it has been shown to have modest benefits in terms of reducing symptoms and duration of hospitalisation
It should not be used because of its side effects in HIV positive patients

30. Rationale for steroid trial Anecdotal reports of symptomatic response
Potential risks in patients with advanced HIV
110 participants (55 each arm)
Life-threatening TB-IRIS was an exclusion
Open-label prednisone at physician discretion if clinical deterioration/relapse
Given this equipoise we conducted the first treatment in TB-IRIS…
We conducted a randomised placebo-controlled trial of prednisone for treating paradoxical TB-IRIS and this was presented at CROI earlier this year.
55 patients were enrolled to each of the two arms - prednisone and placebo.
Patients with immediately life threatening TB-IRIS for example neurological involvement were excluded and treated with prednisone
Study drug was given for 4 weeks, initially at 1.5 mg/kg/d then half that dose
Patients who deteriorated significantly on study drug or relapsed after completing study drug could be switched to open label at physician discretion.
Meintjes et al, AIDS 2010;24:2381

31. Prednisone 1.5mg/kg/day x 2 weeks 0.75mg/kg/day x 2 weeks
HIV-TB patients recently
started ART with
suspected TB-IRIS
Assessed using a clinical
case definition for TB-IRIS
and alternative diagnoses
excluded
Inclusion criteria
Informed consent
Randomised
Prednisone
1.5mg/kg/day x 2 weeks
0.75mg/kg/day x 2 weeks
Identical placebo
1.5mg/kg/day x 2 weeks
0.75mg/kg/day x 2 weeks
Followed for a total of 12 weeks
Primary endpoint: Total number of days hospitalised + outpatients therapeutic procedures
Secondary endpoints included symptom score, CXR score and steroid side effects

32. Primary endpoint Cumulative number of days hospitalized and outpatient therapeutic procedures (counted as 1 additional day), ITT analysis
Placebo
arm
N = 55
Prednisone
P-value
Total days hospitalized
463
282 -
Total number outpatient procedures 28 24
Cumulative primary endpoint (median, IQR)
3 (0-9)
0 (0-3)
0.04
The predefined primary endpoint was a combined endpoint made up of days hospitalisation (463 days in the placebo arm vs 282 in the prednisone arm) and outpatients procedures (31 in the placebo ve 27 in the prednisone arm).
Analysis was by intention to treat
Counting each outpatient procedure as an additional hospital day (an arbitrarily value we had assigned a priori) there were a median 3 days in the placebo arm and 0 in the prednisone arm. This difference reached statistical significance with a p-value of 0.04.
Significant reduction in morbidity associated with prednisone treatment

33. Secondary endpoints
Consistent benefit, maximal in first 4 weeks, across a range of secondary outcome measures
Symptom score
Karnofsky performance score
MOS-HIV questionnaire (quality of life assessment)
Chest radiology score
C-reactive protein
10/55 in prednisone arm relapsed after completing study drug and required re-initiation of prednisone
4 weeks appeared to be too short for these patients
A consistent benefit maximal in the first 4 weeks was also demonstrated across a range of secondary outcome measures: LIST

34. Adverse events Placebo arm Prednisone P-value Death on study 2 (4%)
2 (4%)
3 (5%)
0.65
Corticosteroid side effects while on study drug*
8 (15%)
0.11
Infections while on study drug
17 (31%)
27 (49%)
0.05
Severe infections**
4 (7%)
0.40
In terms of adverse events, there was no difference in mortality,.
Events that could be attributed to steroid side effects such as hypertension, oedema, hyperglyceamia, hypomania and Cushingoid features occurred in similar numbers in both arms.
If only steroid side effects that occurred while on study drug are counted there were 3 in the placebo arm and 8 in the prednsione arm but this was not significantlyy different.
We analysed infections separately and the number of all infections and severe infections were similar between the arms.
Severe infections were classifies as new WHO stage 4 or invasive bacterial infections.
There were no cases of Kaposi’s sarcoma
* Included BP > 140/90, oedema, hyperglycaemia, hypomania,
acne, Cushingoid features, gastritis symptoms
** WHO stage 4 or invasive bacterial infection

35. Serum IL-6: Placebo vs Prednisone (week 0, 2 and 4)
Moving onto the luminex experiments.
We found a significant decrease in serum concentrations of interleukin 6 in prednisone-treated participants after correcting for multiple comparisons at both week 2 and week 4 compared with baseline. The reductions in placebo-treated participants were not significant.
This is consistent with our finding of a rapid CRP reduction in prednisone treated participants, as IL-6 is the major stimulus of CRP production.
This table summarises the luminex findings for all 12 of the cytokines/chemokines that were assayed.
Median values are presented by treatment group and time point.
After correcting for multiple comparisons significant reductions in TNF alpha, IL12, IL6, IL10 and the chemokine IP10 (also known as CXCL10) were demonstrated at week 2 and week 4 in those on prednisone. For interferon gamma a significant reduction in serum concentrations was seen at week 4 but not 2 in those on prednisone. For all of these cytokines no significant reduction in serum concentrations for those on placebo were seen.
For IL-8 and the chemokines MIP 1 a and B no reductions in either treatment group were seen
IL2, IL1B and GMCSF serum concentraions were undetectable in most participants.
Similar reductions seen in TNFα, IFNγ, IL10, IL12 and CXCL10 on prednisone
Meintjes et al, AJRCCM 2012;186:369

36. Corticosteroids for paradoxical TB-IRIS?
Symptom improvement
Reduced hospitalisation
? Survival benefit in life
threatening cases
Potential adverse effects
- Kaposi’s
- Infections
- Metabolic
Diagnostic uncertainty
Thus we demonstrated that prednisone reduced hospitalisation and improved symptoms, relatively modest benefits. We did not demonstrate a mortality benefit but but one should remember that we excluded patients with life threatening TB-IRIS and switched patients with life threatening deterioration to open label prednisone.
Thus it is also possible that there might be a survival benefit in patients with very severe form of TB-IRIS but this has not been studied.
This is clearly not the final word on corticosteroids for IRIS. In making the decision regarding using steroids clinicains also need to weigh up the potential side effects, there was an excess of mild infections in our study, may be greater risks in other settings for instance where strongyloides is endemic. But more importantly in settings where diagnostic capability is limited more harm than good could be done by prescribing corticosteroids to patients who do not have TB-IRIS but another OI or have undiagnosed MDR.

37. CASE: 49 year old HIV+ man with CD4=29, diagnosed with drug-susceptible PTB. Started ART 2 weeks after TB treatment. 2 weeks later developed recurrent TB symptoms, worsening of pulmonary infiltrate and new pleural effusion.
MANAGEMENT: Antibiotic, aspiration of pleural effusion, prednisone. TB cultures of sputum and effusion were negative at TB-IRIS.

38. Needle aspiration

39. Major TB-IRIS risk factors
Low CD4 count
Short interval between TB treatment and ART
Disseminated TB
Lawn AIDS 2007;21:335
Meintjes Lancet Infect Dis 2008;8:516
Burman IJTLD 2007;11:1282

40. When to start ART after recent diagnosis of TB?
Earlier
ART
Deferred
ART
Risk of
IRIS
Risk of HIV
disease progression
MORTALITY
MORTALITY
When to start ART after recent diagnosis of TB?
3 recent large RCTs (SAPIT, STRIDE, CAMELIA)

41. ART timing and primary endpoints
Death
p=0.006
38% 
Death/AIDS
p = 0.45
Death/AIDS
p = 0.73

42. ART timing and primary endpoints in patients with CD4 < 50
Death
p=0.006
38% 
Death/AIDS
p=0.02
42% 
Death/AIDS
p=0.06
68% 
* CAMELIA data represents all patients in trial, majority had CD4 < 50 (median CD4 =25)

43. SAPiT IRIS incidence (IRIS cases/100 person years)
Naidoo,
Annals Intern Med 2012

44. Implications In patients with CD4 < 50: start ART at 2 weeks
Even though more likely to develop IRIS with early ART
Benefit most from early ART in terms of survival and preventing AIDS events
In patients with CD4 > 50
ART can be deferred ~ 8 weeks to reduce risk of IRIS
Except patients with severe clinical disease, organ system dysfunction, low performance score, low BMI or Hb as these are associated with higher mortality

45. Preventing TB-IRIS in high-risk patients: Randomized placebo-controlled trial of prednisone (Pred-ART trial)
Graeme Meintjes, Lut Lynen, Robert J Wilkinson, Gary Maartens, Bob Colebunders, Charlotte Schutz, Shaheed Mattee, Funeka Bango, Jan Kuehne, Zuhoor Dadeker, Christiana Noestlinger, Harry van Loen, Joris Menten, Jozefien Buyze, Edwin Wouters, Bill Burman, Raffaella Ravinetto, Friedrich Thienemann, Liz Blumenthal, Cari Stek, Amanda Jackson, Lorraine Swanepoel, Rene Goliath, Amy Nair
Others?

46. TB TREATMENT (and CO-TRIMOXAZOLE)
ART
ART started within 30 days of TB treatment
Start ART +
4 weeks prednisone
Follow-up for 12 weeks
(Visits at weeks 1,2,4,8 and 12)
HIV-infected
ART-naive
CD4 < 100
TB diagnosed
n = 240
Informed consent
Randomised 1:1
Start ART +
4 weeks placebo
Follow-up for 12 weeks
(Visits at weeks 1,2,4,8 and 12)
Dose of prednisone/placebo: 40mg/day x 2 weeks then 20mg/day x 2 weeks
Primary endpoint: Development of paradoxical TB-IRIS
ClinicalTrials.gov NCT

47. Paradoxical TB-IRIS only occurs in ART naïve patients starting first line ART.
TRUE or FALSE?

48. Acknowledgements Robert Wilkinson Gary Maartens Katalin Wilkinson
Suzaan Marais
Charlotte Schutz
Tasnim Bana
Maia Lesosky
Molebogeng Rangaka
Chelsea Morroni
Tolu Oni
Dominique Pepper
Kevin Rebe
Rene Goliath
Helen van der Plas
Marc Mendelson
Priscilla Mouton
Bob Colebunders
Anali Conesa Botella
Raylene Titus
Keira Skolimowska
Kerryn Matthews
Rebecca Tadokera
Mark Sonderup
Finally I wish to acknowledge other investigators who were not listed on my first slide and our funders. Thank you.

49. Pred-ART funders